Transdermal porator and patch system and method for using same

ABSTRACT

A transdermal permeant delivery system for delivery of at least one permeant composition into a tissue membrane of a subject including a disposable substrate having at least a portion of a bottom surface of a first release liner connected to an upper surface of the substrate and a patch having a backing layer and a reservoir that is selectively removable from the top surface of the first release liner. In a connected position, a first portion of the backing layer of the patch is releaseably mounted to a top surface of the first release liner in spaced registration with a poration area of the substrate.

This application claims priority to U.S. Provisional Application No.60/886,039, filed on Jan. 22, 2007 and is a continuation-in-part of U.S.patent application Ser. No. 10/384,763, filed on Mar. 11, 2003, whichalso claims priority to U.S. Provisional Application No. 60/363,022,filed on Mar. 11, 2002. These applications are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

This invention relates to a system and method for transdermal deliveryof drugs or other permeants through the skin of a subject. Moreparticularly, this invention relates to a system and method for thecreation of small holes or perforations or micropores in a biologicalmembrane of the subject and the subsequent transdermal delivery of drugsor other permeants into the subject via the formed micropores.

BACKGROUND

The stratum corneum is chiefly responsible for the barrier properties ofskin. Thus, it is this layer that presents the greatest barrier totransdermal flux of drugs or other molecules into the body and ofanalytes out of the body. The stratum corneum, the outer horny layer ofthe skin, is a complex structure of compact keratinized cell remnantsseparated by lipid domains. Compared to the oral or gastric mucosa, thestratum corneum is much less permeable to molecules either external orinternal to the body. The stratum corneum is formed from keratinocytes,which comprise the majority of epidermal cells that lose their nucleiand become corneocytes. These dead cells comprise the stratum corneum,which has a thickness of only about 10-30 microns and protects the bodyfrom invasion by exogenous substances and the outward migration ofendogenous fluids and dissolved molecules. The stratum corneum iscontinuously renewed by shedding of corneum cells during desquaminationand the formation of new corneum cells by the keratinization process.Historically, the majority of drugs have been delivered orally or byinjection. However, neither the oral or injection route is well-suitedfor continual delivery of drugs over an extended period of time.Further, the injection method of administration is inconvenient anduncomfortable; additionally, needles continue to pose a hazard aftertheir use. Therefore, transdermal drug delivery to the body has been apopular and efficacious method for delivering a limited number ofpermeants into an organism.

To enhance transdermal drug delivery, there are known methods forincreasing the permeability of the skin to drugs. For example, U.S. Pat.No. 5,885,211 is directed to thermal microporation techniques anddevices to form one or more micropores in a biological membrane andmethods for selectively enhancing outward flux of analytes from the bodyor the delivery of drugs into the body. PCT WO 00/03758, published Jan.27, 2000, is directed to methods and apparatus for forming artificialopenings in a selected area of a biological membrane using a pyrotechnicelement that, when triggered, explodes in a controlled fashion so thatthe micro-explosion produces the artificial opening in the biologicalmembrane to a desired depth and diameter. PCT WO98/29134, published Jul.9, 1998 discloses a method of enhancing the permeability of a biologicalmembrane, such as the skin of an animal, using microporation and anenhancer such as a sonic, electromagnetic, mechanical, thermal energy orchemical enhancer. Methods and apparatus for delivery or monitoringusing microporation also are described in PCT WO 99/44637, publishedSep. 10, 1999; U.S. Pat. No. 6,022,316; PCT WO 99/44508, published Sep.10, 1999; PCT WO 99/44507, published Sep. 10, 1999; PCT WO 99/44638,published Sep. 10, 1999; PCT WO 00/04832, published Feb. 3, 2000; PCT WO00/04821, published Feb. 3, 2000; and PCT WO 00/15102, published Mar.23, 2000. Applicants would note that all publications, patents andpatent applications referred to herein, such as those above, areincorporated herein by reference in their entirety.

There remains a need for improved methods and devices for transdermaldelivery of permeants such as, for example, drugs, bio-activecompositions, and the like.

SUMMARY

According to one embodiment of the invention, a system and method fortransdermal permeant delivery of at least one permeant into a tissuemembrane of a subject is provided. In one aspect, the transdermalpermeant delivery system comprises a disposable substrate, a firstrelease liner, and a patch that is selectively removable from a topsurface of the first release liner. The substrate defines a porationarea that is configured for forming micropores in the tissue membrane ofthe subject. In another aspect, at least a portion of a bottom surfaceof the first release liner is connected to an upper substrate surface ofthe substrate. In a further exemplary aspect, the patch comprises abacking layer and a reservoir mounted thereon a portion of a lowersurface of the backing layer that is configured for releaseablycontaining the at least one permeant. In a connected position, in whichthe patch is mounted to the first release liner, a first portion of thebacking layer is releaseably mounted thereto the top surface of thefirst release liner in spaced registration with the poration area of thesubstrate. In another aspect, a second portion of the backing layer isfolded back about a fold into a folded position when the patch is in theconnected position such that the lower surface of the second portion ofthe backing layer faces outwardly away from the upper substrate surfaceof the substrate.

Other apparatus, methods, and aspects and advantages of the inventionwill be discussed with reference to the Figures and to the detaileddescription of the preferred embodiments.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several aspects described belowand together with the description, serve to explain the principles ofthe invention. Like numbers represent the same elements throughout thefigures.

FIG. 1 is a perspective view of a transdermal permeant delivery systemshowing a first embodiment of a transdermal patch of the presentinvention mounted thereon an embodiment of a disposable substrate.

FIG. 2 is a perspective view of an exemplary embodiment of an applicatorof the present invention.

FIG. 3 is perspective view of the delivery system of FIG. 1 releasablyconnected to the applicator of FIG. 2.

FIG. 4 is an exploded view of the first embodiment of the transdermalpatch of FIG. 1.

FIG. 5 is an exploded view of a second embodiment of the transdermalpatch of the present invention.

FIG. 6 is an exploded view of a third embodiment of the transdermalpatch of the present invention.

FIG. 7 is an exploded view of an embodiment of the substrate of thetransdermal delivery system, showing a ridge extending outwardly fromthe upper substrate surface.

FIG. 8 is a top elevational view of the substrate of FIG. 7.

FIG. 9 is a bottom elevational view of the substrate of FIG. 8.

FIG. 10 is a top elevational view of one embodiment of a filament array.

FIG. 11 is an enlarged cross sectional view of the filament array takenacross line 11 of FIG. 10.

FIG. 12 is a perspective view of the filament array of FIG. 10.

FIG. 13 is a cross-sectional view of the filament taken across line 13of FIG. 12.

FIGS. 14A-C are schematic views of exemplary balanced filament arrays.

FIG. 15 is a schematic, partly sectional view of an exemplary means forforming micropores in a tissue membrane.

FIG. 16 is a schematic view of an electrode assembly of the means forforming micropores in a tissue membrane of FIG. 15.

FIG. 17 is a perspective schematic view of the transdermal permeantdelivery system of FIG. 1 shown connected to the skin of the subjectprior to the poration of the skin of the subject.

FIG. 18 is a perspective schematic view of the transdermal permeantdelivery system showing the transdermal patch being separated from aportion of the transdermal permeant delivery system after poration ofthe subject's skin.

FIG. 19 is a perspective schematic view of the transdermal patchpositioned in registration with the porated area of the subject's skin.

FIG. 20 is an exploded view of a fourth embodiment of the transdermalpatch of the present invention.

FIG. 21 is an exploded view of a fifth embodiment of the transdermalpatch of the present invention.

FIG. 22 is a perspective schematic view of the transdermal permeantdelivery system of FIG. 21 showing the transdermal patch after beingseparated from a portion of the transdermal permeant delivery systemafter poration of the subject's skin.

FIG. 23 is a perspective schematic view of the transdermal permeantdelivery system showing the transdermal patch after the reservoir of thepatch is folded into registration with the formed micropores.

FIG. 24 is a perspective schematic view of the transdermal permeantdelivery system showing removable portions of the transdermal permeantdelivery system being separated from the transdermal patch.

FIG. 25 shows an exemplary schematic of an applicator circuit.

FIG. 26 shows an exemplary schematic of an exemplary power circuit forthe applicator.

FIG. 27 shows an exemplary schematic of a bias power block diagram.

FIG. 28 shows an exemplary schematic of a microprocessor block diagram.

FIG. 29 shows an exemplary schematic of a vacuum circuit block diagram.

FIG. 30 schematically illustrates an exemplary a top level behavioralflow diagram of the applicator.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be understood more readily by reference to thefollowing detailed description, examples, drawing, and claims, and theirprevious and following description. However, before the present devices,systems, and/or methods are disclosed and described, it is to beunderstood that this invention is not limited to the specific devices,systems, and/or methods disclosed unless otherwise specified. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

The following description of the invention is provided as an enablingteaching of the invention in its best, currently known embodiment. Tothis end, those skilled in the relevant art will recognize andappreciate that many changes can be made to the various aspects of theinvention described herein, while still obtaining the beneficial resultsof the present invention. It will also be apparent that some of thedesired benefits of the present invention can be obtained by selectingsome of the features of the present invention without utilizing otherfeatures. Accordingly, those who work in the art will recognize thatmany modifications and adaptations to the present invention are possibleand can even be desirable in certain circumstances and are a part of thepresent invention. Thus, the following description is provided asillustrative of the principles of the present invention and not inlimitation thereof.

As used throughout, the singular forms “a,” “an,” and “the” includeplural referents unless the context clearly dictates otherwise. Thus,for example, reference to “a filament” can include two or more suchfilaments unless the context indicates otherwise.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, a “tissue membrane” can be any one or more epidermallayers of a subject. For example, in one aspect, the tissue membrane isa skin layer that includes the outermost layer of the skin, i.e., thestratum corneum. In an alternative aspect, a skin layer can include oneor more backing layers of the epidermis, commonly identified as stratumgranulosum, stratum malpighii, and stratum germinativum layers. It willbe appreciated by one of ordinary skill in the art that there isessentially little or no resistance to transport or to absorption of apermeant through the backing layers of the epidermis. Therefore, in oneaspect of the present invention, an at least one formed pathway in askin layer of a subject is a pathway in the stratum corneum layer of asubject. Further, as used herein, “stratum corneum” refers to theoutermost layer of the skin, consisting of from about 15 to about 20layers of cells in various stages of drying out. The stratum corneumprovides a barrier to the loss of water from inside the body to theexternal environment and from attack from the external environment tothe interior of the body. Still further, as used herein, “tissuemembrane” can refer to an aggregate of cells of a particular kind,together with their intercellular substance, that forms a structuralmaterial. At least one surface of the tissue membrane must be accessibleto the device. As noted above, the preferred tissue membrane is theskin. Other tissues suitable for use with this invention include mucosaltissue and soft organs.

As used herein, the term, “subcutaneous fluid” can include, withoutlimitation, moisture, plasma, blood, one or more proteins, interstitialfluid, and any combination thereof. In one aspect, a subcutaneous fluidaccording to the instant invention is a moisture source comprisingwater.

As used herein, “poration,” “microporation,” or any such similar termmeans the formation of a small hole or crevice (subsequently alsoreferred to as a “micropore”) in or through the tissue or biologicalmembrane, such as skin or mucous membrane, or the outer layer of anorganism to lessen the barrier properties of this biological membranefor the passage of at least one permeant from one side of the biologicalmembrane to the other for select purposes. Preferably the hole or“micropore” so formed is approximately 1-1000 microns in diameter andextends into the biological membrane sufficiently to break the barrierproperties of the stratum corneum without adversely affecting theunderlying tissues. It is to be understood that the term “micropore” isused in the singular form for simplicity, but that the device of thepresent invention may form multiple artificial openings. Poration couldreduce the barrier properties of a biological membrane into the body forselected purposes, or for certain medical or surgical procedures. Forthe purposes of this application, “poration” and “microporation” areused interchangeably and mean the same thing.

A “microporator” or “porator” is a component for a microporation devicecapable of microporation. Examples of a microporator or porator include,but are not limited to, a filament capable of conductively deliveringthermal energy via direct contact to a biological membrane to cause theablation of some portion of the membrane deep enough to form amicropore, an optically heated topical dye/absorber layer, anelectromechanical actuator, a microlancet, an array of microneedles orlancets, a sonic energy ablator, a laser ablation system, ahigh-pressure fluid jet puncturer, and the like. As used herein,“microporator” and “porator” are used interchangeably.

As used herein, “penetration enhancement” or “permeation enhancement”means an increase in the permeability of the biological membrane to adrug, bio-active composition, or other chemical molecule, compound,particle or substance (also called “permeant”), i.e., so as to increasethe rate at which the drug, bio-active composition, or other chemicalmolecule, compound or particle permeates the biological membrane.

As used herein, “enhancer,” “chemical enhancer,” “penetration enhancer,”“permeation enhancer,” and the like includes all enhancers that increasethe flux of a permeant, analyte, or other molecule across the biologicalmembrane, and is limited only by functionality. In other words, all cellenvelope disordering compounds and solvents and any other chemicalenhancement agents are intended to be included. Additionally, all activeforce enhancer technologies such as the application of sonic energy,mechanical suction, pressure, or local deformation of the tissues,iontophoresis or electroporation are included. One or more enhancertechnologies may be combined sequentially or simultaneously. Forexample, a chemical enhancer may first be applied to permealize thecapillary wall and then an iontophoretic or sonic energy field may beapplied to actively drive a permeant into those tissues surrounding andcomprising the capillary bed.

As used herein, “transdermal” means passage of a permeant into andthrough the biological membrane.

As used herein, the term “permeant,” “drug,” “permeant composition,” or“pharmacologically active agent” or any other similar term are usedinterchangeably to refer to any chemical or biological material orcompound suitable for transdermal administration by the methodspreviously known in the art and/or by the methods taught in the presentinvention, that induces a desired biological or pharmacological effect,which may include but is not limited to (1) having a prophylactic effecton the organism and preventing an undesired biological effect such as aninfection, (2) alleviating a condition caused by a disease, for example,alleviating pain or inflammation, and/or (3) either alleviating,reducing, or completely eliminating the disease from the organism. Theeffect may be local, such as providing for a local anesthetic effect, orit may be systemic. Such substances include broad classes of compoundsnormally delivered into the body, including through body surfaces andmembranes, including skin. In general, for example and not meant to belimiting, such substances can include any drug, chemical, or biologicalmaterial that induces a desired biological or pharmacological effect. Tothis end, in one aspect, the permeant can be a small molecule agent. Inanother aspect, the permeant can be a macromolecular agent. In general,and without limitation, exemplary permeant include, but are not limitedto, anti-infectives such as antibiotics and antiviral agents; analgesicsand analgesic combinations; anorexics; antihelminthics; antiarthritics;antiasthmatic agents; anticoagulant; anticonvulsants; antidepressants;antidiabetic agents; antidiarrheals; antihistamines; antiinflammatoryagents; antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics;antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including potassium and calciumchannel blockers, beta-blockers, alpha-blockers, and antiarrhythmics;antihypertensives; diuretics and antidiuretics; vasodilators includinggeneral coronary, peripheral, and cerebral; central nervous systemstimulants; vasoconstrictors; cough and cold preparations, includingdecongestants; hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers.

The devices and methods of the instant invention can also be used totransdermally deliver peptides, polypeptides, proteins, or othermacromolecules known to be difficult to convey across the skin withexisting conventional techniques because of their size. Thesemacromolecular substances typically have a molecular weight of at leastabout 300 Daltons, and more typically, in the range of about 300 to40,000 Daltons. Examples of polypeptides and proteins which may bedelivered in accordance with the present invention include, withoutlimitation, antibodies, LHRH, LHRH analogs (such as goserelin,leuprolide, buserelin, triptorelin, gonadorelin, napharelin andleuprolide), GHRH, GHRF, insulin, insulinotropin, calcitonin,octreotide, endorphin, TRH, NT-36 (chemical name:N-[[(s)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate,etc.), follicle luteoids, alpha-ANF, growth factor such as releasingfactor (GFRF), beta-MSH, GH, somatostatin, bradykinin, somatotropin,platelet-derived growth factor, asparaginase, bleomycin sulfate,chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin(ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor),glucagon, hirudin and hirudin analogs such as hirulog, hyaluronidase,interleukin-2, menotropins (urofollitropin (FSH) and LH), oxytocin,streptokinase, tissue plasminogen activator, urokinase, vasopressin,desmopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensinII antagonists, antidiuretic hormone agonists, antidiuretic hormoneantagonists, bradykinin antagonists, CD4, ceredase, CSI's, enkephalins,FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors,colony stimulating factors, parathyroid hormone and agonists,parathyroid hormone antagonists, prostaglandin antagonists, cytokines,lymphokines, pentigetide, protein C, protein S, renin inhibitors,thymosin alpha-1, thrombolytics, TNF, GCSF, EPO, PTH, heparin having amolecular weight from 3000 to 12,000 Daltons, vaccines, vasopressinantagonist analogs, interferon-alpha, -beta, and -gamma, alpha-1antitrypsin (recombinant), and TGF-beta genes; peptides; polypeptides;proteins; oligonucleotides; nucleic acids; and polysaccharides.

Further, as used herein, “peptide”, means peptides of any length andincludes proteins. The terms “polypeptide” and “oligopeptide” are usedherein without any particular intended size limitation, unless aparticular size is otherwise stated. Exemplary peptides that can beutilized include, without limitation, oxytocin, vasopressin,adrenocorticotrophic hormone, epidermal growth factor, prolactin,luliberin or luteinising hormone releasing hormone, growth hormone,growth hormone releasing factor, insulin, somatostatin, glucagon,interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin,calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin,bacitracins, polymixins, colistins, tyrocidin, gramicidines, andsynthetic analogues, modifications and pharmacologically activefragments thereof, monoclonal antibodies and soluble vaccines. It iscontemplated that the only limitation to the peptide or protein drugwhich may be utilized is one of functionality.

Examples of peptide and protein drugs that contain one or more aminogroups include, without limitation, anti-cancer agents, antibiotics,anti-emetic agents, antiviral agents, anti-inflammatory and analgesicagents, anesthetic agents, anti-ulceratives, agents for treatinghypertension, agents for treating hypercalcemia, agents for treatinghyperlipidemia, etc., each of which has at least one primary, secondaryor tertiary amine group in the molecule, preferably, peptides, proteinsor enzymes such as insulin, calcitonin, growth hormone, granulocytecolony-stimulating factor (G-CSF), erythropoietin (EPO), bonemorphogenic protein (BMP), interferon, interleukin, platelet derivedgrowth factor (PDGF), vascular endothelial growth factor (VEGF),fibroblast growth factor (FGF), nerve growth factor (NGF), urokinase,etc. can be mentioned. Further examples of protein drugs include,without limitation, insulin, alpha-, beta-, and gamma-interferon, humangrowth hormone, alpha- and beta-1-transforming growth factor,granulocyte colony stimulating factor (G-CSF), granulocyte macrophagecolony stimulating factor (G-MCSF), parathyroid hormone (PTH), human orsalmon calcitonin, glucagon, somatostatin, vasoactive intestinal peptide(VIP), and LHRH analogs.

As used herein, an “effective” amount of a pharmacologically activeagent means an amount sufficient to provide the desired local orsystemic effect and performance at a reasonable benefit/risk ratioattending any medical treatment. An “effective” amount of a permeationor chemical enhancer as used herein means an amount selected so as toprovide the desired increase in biological membrane permeability, thedesired depth of penetration, rate of administration, and amount of drugdelivered.

Embodiments of the present invention are described below with referenceto block diagrams and flowchart illustrations of methods, apparatuses(i.e., systems) and computer program products according to an embodimentof the invention. It will be understood that each block of the blockdiagrams and flowchart illustrations, and combinations of blocks in theblock diagrams and flowchart illustrations, respectively, can beimplemented by computer program instructions. These computer programinstructions may be loaded onto a general purpose computer, specialpurpose computer, or other programmable data processing apparatus toproduce a machine, such that the instructions which execute on thecomputer or other programmable data processing apparatus create a meansfor implementing the functions specified in the flowchart block orblocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including computer-readableinstructions for implementing the function specified in the flowchartblock or blocks. The computer program instructions may also be loadedonto a computer or other programmable data processing apparatus to causea series of operational steps to be performed on the computer or otherprogrammable apparatus to produce a computer-implemented process suchthat the instructions that execute on the computer or other programmableapparatus provide steps for implementing the functions specified in theflowchart block or blocks.

Accordingly, blocks of the block diagrams and flowchart illustrationssupport combinations of means for performing the specified functions,combinations of steps for performing the specified functions and programinstruction means for performing the specified functions. It will alsobe understood that each block of the block diagrams and flowchartillustrations, and combinations of blocks in the block diagrams andflowchart illustrations, can be implemented by special purposehardware-based computer systems that perform the specified functions orsteps, or combinations of special purpose hardware and computerinstructions.

Referring to the figures, the present invention for a transdermalpermeant delivery system comprises a system and method for painlesslycreating microscopic holes, i.e., micropores, from about 1 to about 1000microns in diameter in the biological membrane of a subject, such as,for example, and not meant to be limiting, the stratum corneum of humanskin. The system allows for a rapid and painless method of eliminatingthe barrier function of the stratum corneum to facilitate thetranscutaneous transport of therapeutic substances into the body via theformed micropores when applied topically to the poration site.

In one embodiment, the transdermal permeant delivery system 10 comprisesan applicator 20, a substrate 40 that comprises a portion of a means forforming at least one micropore, and a registerable patch 100 that isconfigured to contain at least one permeant. In one aspect, theapplicator 20 comprises a body 22 that defines an interior cavity 24 anda portion of the means for forming at least one micropore. In thisexemplary aspect, the portion of the means for forming at least onemicropore of the applicator 20 can comprise a controller 26 comprisingdriving electronics such as, for example, an electrical circuit boardand a power source, such as, for example a battery. In this aspect, thecontroller 26 is positioned within the interior cavity of the body. Inan exemplary aspect, the controller is configured to provide a stimulusto the means for forming the at least one micropore that is positionedtherein the substrate 40 to initiate formation of the at least onemicropore upon user command. In alternative aspects, the stimulus cancomprise an electrical driving current, such as, for example and notmeant to be limiting, a pulsed electrical current, a RF pulse, and thelike, when an actuator button 28 is actuated by a user of the system.Optionally, the controller 26 is configured to provide a thermal pulsewhen the actuator button is pressed.

In a further aspect, the applicator 20 comprises an interface 30 that isconfigured for securely and releasably mounting the substrate 40thereto. The applicator interface can comprise an anode 31 and a cathode32 that are in electrical communication with respective portions of themeans for forming the at least one micropore when the substrate ismounted to the interface. In one aspect, the anode and cathode extendoutwardly from the interface 30 of the applicator. Optionally, the anodeand the cathode can be pins that extend from the interface of theapplicator to from two exposed electrodes.

In another aspect, the applicator 20 can further comprise a source ofvacuum 33, such as, for example, a vacuum pump. In this aspect, it iscontemplated that the interface 30 defines a first port 34 that is incommunication with the source of vacuum. Further, the interface 30 ofthe applicator 20 can comprise a gasket 36 mounted about the first portof the interface. Optionally, the interface can define a second port 35that is in communication with a vacuum sensor 37. In this aspect, it iscontemplated that the respective first and second ports are surroundedby the gasket.

The substrate 40 of the system can comprise an upper substrate surface42, a lower substrate surface 44 and a defined poration area 46. In oneaspect, the poration area defines an area on the upper substrate surface42 upon which at least a portion of a means for forming at least onemicropore is positioned. Thus, in operation, the micropores formed bythe system of the present invention will be confined to those portionsof the tissue membrane that underlie the poration area of the substrate.

In one aspect, the substrate 40 can have at least one male tab 46 thatextends outwardly from a peripheral edge portion 50 of the substrate.Further, a portion of the peripheral edge of the substrate can compriseat least one bias element 52. In one exemplary aspect, the at least onebias element 52 comprises at least one partial leaf spring member 52′,52″ that is positioned to articulate generally within the plane of thesubstrate. Optionally, the at least one male tab can be positioned onthe peripheral edge of the substrate such that is positioned generallybetween a pair of bias elements. In a further aspect, the substratedefines an opening 54 that is positioned generally opposite to the atleast one bias element and, optionally, generally opposite to the atleast one male tab 46. In this aspect, the interface 30 of theapplicator 20 comprises a lip 38 and at least one slot 39 that areconfigured to operatively engage the respective at least one biaselement and the at least one male tab of the substrate. In a furtheraspect, the interface 30 comprises a male finger 41 that extendsoutwardly from the face of the interface. In this aspect, the malefinger can be positioned generally opposite to the at least one slot 39.One skilled in the art will appreciate that the cooperative relationshipbetween the at least one bias element 52, the at least one male tab 46,and the opening 54 of the substrate 40 and the lip 38, the at least oneslot 39, and the male finger 41 of the interface facilitates a user'sability to easily mount and remove the substrate from the interface ofthe applicator.

In a further aspect, the substrate 40 defines a conduit 56 that extendsbetween the lower and upper substrate surfaces. In this aspect, one openend 58 of the conduit is defined on the poration area 46 that is formedon the upper substrate surface 42 of the substrate. In another aspect,the substrate 40 defines at least one channel 60 on the upper substratesurface 42. It is contemplated that the at least one channel will beformed therein the poration area of the substrate. In this aspect, theat least one channel 60 is in fluid communication with the conduit. Whenthe substrate 40 is mounted to the interface 30, the open end 59 of theconduit defined on the lower substrate surface 44 is configured to bepositioned in fluid communication with the port 34 of the interface. Inone operational aspect and as one skilled in the art will appreciate,the gasket 36 helps to form a fluid tight seal between the respectivefirst and second ports of the applicator 20 and the conduit 56 of thesubstrate when the source of vacuum 33 is actuated.

Optionally, the substrate 40 can comprises a ridge 41 defined on theupper substrate surface 42 that, in one embodiment, extends generallyoutwardly from the upper substrate surface. In one aspect, the ridgeextends peripherally about at least a portion of the poration area ofthe substrate. In a further exemplary aspect, the ridge is continuousand substantially surrounds the poration area. In use, the exemplaryridge can act as a sealing member formed between the biological membraneand the substrate when the source of vacuum is actuated and communicatedto the poration area via the conduit and the channels. Thus, the ridgecan aid in minimizing the amount of vacuum required to draw thebiological membrane into substantial conformal contact with the meansfor forming at least one micropore that is positioned therein theporation area.

In a further aspect, the substrate 40 can optionally define a femaledepression 48 on a portion of the upper substrate surface that extendsfrom a portion of the peripheral edge of the substrate inwardly towardthe poration area of the substrate. In this aspect, the edges of thefemale depression in the upper substrate surface can form the ridge 41.Optionally, at least a portion of the ridge 41 of the female depression48 can be spaced a predetermined distance from the poration area 46 ofthe substrate. In another aspect, the female depression can besubstantially planar.

In alternative aspects, the means for forming at least one microporecomprises at least one filament that can comprise, for example and notmeant to be limiting, a wire conductor, a deposited conductive material,a machined conductive material, a laser conductive material, an adhesivefoil, an electroplated material, a screen-printed material, and etchedconductive material, and the like. In a further aspect the at least onefilament can comprise a filament array having a plurality of filaments.Various methodologies for forming filament arrays suitable for use inthe system of the present invention are described in U.S. Pat. Nos.6,692,456 and 7,141,034 to Eppstein, et al., all of which areincorporated herein by reference in their entirety.

Optionally, the means for forming at least one micropore can comprise,for example and not meant to be limiting, a filament capable ofconductively delivering thermal energy via direct contact to the tissuebiological membrane to cause the ablation of some portion of thatmembrane deep enough to form the micropore, a probe element capable ofdelivering electrical energy via direct contact to a tissue membrane tocause ablation of some portion of said membrane deep enough to form themicropore, an electro-mechanical applicator, a microlancet, an array ofmicroneedles or lancets, a sonic energy ablator, a laser ablationsystem, and a high-pressure fluid jet puncturer as described in U.S.Pat. Nos. 5,885,211 to Eppstein, et al., 6,527,716 to Eppstein, et al.,and pending U.S. Published application Ser. No. 11/081,448, all of whichare incorporated herein by reference in their entirety.

In a further exemplary aspect and as shown in FIGS. 10-14C, the meansfor forming at least one micropore comprises a filament array 70 thathas a plurality of filaments 72 formed therein. In this aspect, eachfilament 72 is configured for conductively delivering thermal energy viadirect contact to the tissue biological membrane to cause the ablationof some portion of that membrane deep enough to form the micropore.

In one exemplary aspect, the filament array 70 is mounted to a portionof the upper substrate surface 42. Optionally, an adhesive layer 73 canbe mounted to a portion of the upper substrate surface and is configuredto allow for the mounting of the electrically isolated portions of thefilament array, i.e, the adhesive layer 73 is interposed between theupper substrate surface and portions of the electrically isolatedportions of the filament array. In this aspect, it is contemplated thatthe adhesive layer 73 defines a pair of openings that are configured toallow the passage of the anode 31 and cathode 32 when the substrate isconnected to the applicator. In operation, the adhesive layer 73, isconnected to a portion of the bottom surface of the respectiveelectrically isolated portions of the filament array and the portion ofthe upper substrate surface. This connection is configured to minimizepossible vacuum loss through the ports 45 in the substrate that extendfrom the lower substrate surface (which are described in more detailbelow) when vacuum is supplied to the substrate.

In another aspect, the substrate 40 can further comprise a backing 74that is configured to mount to and overlie at least a portion of the topsurface 71 of the filament array such that a portion of the filamentarray in the poration area 46 is exposed. In this aspect, the filaments72 are exposed such that they can be brought into intimate contact withbody tissue. In another aspect, the backing 74 can act to electricallyisolate portions of the filament array. In a further aspect, thesubstrate can comprise an adhesive layer 76 that is disposed between thebacking and the filament array.

In another exemplary aspect, the filament array is substantiallyenclosed in the substrate. One would appreciate however that in thisaspect, the portion of the filament array in the poration area isexposed. As noted above, the filaments are exposed such that they can bebrought into intimate contact with body tissue.

In a further aspect, the filament array 70 can be, for example and notmeant to be limiting, a bi-clad foil 80 comprising a conductive layer 82and a resistive layer 84. In one aspect, the materials that the bi-cladfoil is formed from can comprise, for example but not limited to:conductive material such as aluminum, copper, silver, gold, carbon,bronze, false bronze, or the like, and resistive material such astitanium, titanium nitride, tantalum, tantalum nitride, chromium, acarbon compound, tungsten, manganese, nichrom, nickel, platinum,evanohm, polysilicon, stainless steel, or the like. In one exemplaryaspect, the bi-clad foil 80 comprises a conductive layer of copper andan underlying resistive layer of stainless steel.

In one exemplary aspect, the filament array 70 can be formed by aphotochemical wet etching process in which an etch resist, for exampleand not meant to be limiting, a positive or negative acting liquid,dryfilm or powder resist, is selectively applied to the bi-clad foil viaconventional methods, such as, for example, liquid coating, lamination,electrodeposition, and the like. The resist-coated foil is then exposedto UV light through a negative or positive photo-tool, creating thedesired pattern. Exposed areas are cross-linked and etch-resistant,whereas non-exposed areas can be removed to expose the foil for etching.

In one example, the etching is a two-step process. In the first step,for an exemplary stainless steel/copper bi-clad foil, both metals of thebi-clad foil are etched simultaneously. In this aspect, all features onthe stainless steel side of the bi-clad foil are etched to specificationand features on the copper side are etched partially. The second etchingstep etches the conductive copper traces to specification andsubstantially removes all of the copper residues from the backside ofthe filaments. At the completion of the second etching step, thefilaments are formed substantially of the stainless steel material,which are highly resistant. In one aspect, the etching process resultsin the removal of all of the material from between the filaments, andcan optionally produce some undercutting of the relatively wide feedertraces.

Optionally, an optical machining station, or other suitablemicromachining techniques such as diamond milling, electron beametching, or the like, selectively removes portions of the conductivelayers and resistive layer of the bi-clad foil to create a pattern offeeder traces and filaments. The use of a laser may be advantageous insome applications as it only requires one step and can be designed toform the programmed patterns rapidly in the resistive layer, as thislayer is typically thinner than the conductive layer, and/or morephoto-absorbent. Optionally, an adhesive film can be applied to anylayer, and a laser machining station used to remove material to form amask for etching. In another aspect, an adhesive film can be applied tothe bi-clad foil and a laser machining station is used to removematerial to form a mask for etching the desired pattern in the bi-cladfoil below the exposed portions of the mask.

In a further aspect, and without limitation, the bi-clad foil 80 can beproduced by a cold-rolling, low-pressure process, by reduction-coldrolling, by reduction-hot rolling, explosion-bonding, plating, and thelike. The bi-clad foil can be between about 10 μm to about 300 μm in athickness (t) dimension, including additional nominal thicknesses of 20,30, 40, 50 ,60 ,70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180,190, 200, 210, 220, 230, 240, 250, 260, 270, 280, and 290 μm, with 105μm being one preferred thickness. In one aspect, it is contemplated thatthe filaments are substantially uniform. Optionally, the filaments canbe non-uniform. Further, it is contemplated that the filaments have asubstantially similar thermal mass. In one exemplary aspect, the width(w) of each filament 72, transverse to the longitudinal axis of thefilament, can range between about 30 to 150 μm, including additionalnominal widths of 35, 40, 35, 50, 55, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, 135, 140, and 145 μm, with a range ofbetween about 45 and 55 μm or between 115 and 125 μm being preferred.Similarly, in another exemplary aspect, each filament 74 has a length(l) extending along the longitudinal axis of the filament, of betweenabout 200 to 700 μm, with additional lengths of 250, 300, 350, 400, 450,500, 550, 600, and 650 μm, with 500 μm being preferred.

Optionally, the layer of stainless steel can comprise between about 5 toabout 25 percent of the thickness of the bi-clad foil, includingadditional amounts as 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,17%, 18%, 19%, 20%, 21%, 22%, 23%, and 24%, and including any range ofthickness percentages derived from these values.

In a further aspect and referring to FIGS. 14A-14C, the filament array70 comprises means for distributing energy to the filaments of thefilament array. In one exemplary aspect, the means for distributingenergy to the filaments comprises at least one electrical bank 86.Optionally, the at least one electrical bank comprises a plurality ofelectrical banks 86′, 86″. In this aspect, each electrical bank hasassociated filaments 72. In one aspect of the means for distributingenergy, the poration area 46 has a first portion and an opposite and/ormirrored second portion in which portions of each respective electricalbank are positioned in both the first and second portions of theporation area. In this example, the banks are geometrically shaped sothat filaments of one bank are present in both “halves” or portions ofthe active poration area. It will be appreciated that alternativegeometrically shaped banks 86 can be used such that the respective banksare distributed between respective portions of the active poration area.One skilled in the art will note that the use of such electrical banksmakes the filament array 70 less sensitive to small differences in theindividual filament composition and dimensions

In another aspect, the substrate 40 defines a pair of ports 45 in thelower substrate surface 44 that expose respective electrically isolatedportions of the filament array. In one aspect, the ports 45 areconfigured to accept the anode 31 and cathode 32 of the applicator 20when the substrate is mounted to the interface 30 of the applicator suchthat the anode and cathode are in contact with the respectiveelectrically isolated portion of the filament array. Thus, the filamentarray 70 can be placed in electrical communication with the applicator20 when the substrate 40 is received onto the interface 30 so thatelectrical energy can be passed from the applicator, via the anode andcathode and the respective banks 86, to each of the filaments 72 of thefilament array 70.

In a further exemplary aspect and as shown in FIGS. 15 and 16, the meansfor forming at least one micropore comprises a plurality of pairedelectrodes. In this aspect, each pair of electrodes are configured fordelivering electrical energy via direct contact to the tissue biologicalmembrane to cause the electrical ablation of some portion of thatmembrane deep enough to form the micropore. For example, U.S. Pat. Nos.5,885,211, 6,148,232, 6,615,079, and 6,711,435, the disclosures of whichare incorporated herein by reference in their entirety, describe methodsand devices for applying electrical energy between two or more of aplurality of electrodes, which are applied to a subject's skin, in orderto cause ablation of the tissue in an area between the respectiveelectrodes.

In one exemplary aspect, the means for forming at least one microporefurther comprises a control unit 90 that is attachable to the pluralityof electrodes, which is preferably fixed to a suitable area of asubject's skin. The means for forming at least one micropore canadminister an active substance through the normallysubstantially-impermeable stratum corneum layer of the skin by passing acontrolled electric current between the plurality of electrodes, whichablates the stratum corneum and generates micro-channels through whichthe substance can pass.

In one aspect, when means for forming at least one micropore drivescurrent through the stratum corneum, the affected tissue is heatedresistively, so that the tissue is ablated by the total energydissipated therein when a sufficient quantity of energy has passedtherethrough in a short time period. The ablation creates the desiredmicropores in the form of micro-channels in the tissue. In an additionalaspect, the application of a current to a small area of the skin leadsto formation of micro-channels that can be sized to allow for even largemolecules to pass relatively freely, without the necessity of ionizingor polarizing the molecules, and without causing pain or substantialtrauma to the dermis and epidermal tissue underlying the stratumcorneum.

In one aspect, the control unit 90 comprises a switching unit 91, abattery 92 (such as a lithium coin cell battery), and an optionaluser-interface comprising buttons 93 and a sensible signal generator 94,which may comprise a display and/or a buzzer. In one exemplified aspect,the buttons 93 initialize and terminate delivery of the activesubstance.

FIG. 16 shows an array 95 of electrodes 96 that comprises sixteenelectrodes. It is of course contemplated that the array might besmaller, while in others the array might be larger, for example 50×50 oreven more, so as to enable a greater amount of the active substance tobe delivered. In the illustrated aspect, the electrodes 96 in thisembodiment are preferably organized into eight electrode pairs 97, suchthat most of the charge leaving one electrode in a pair goes to theother electrode in that respective pair and generally does not go toelectrodes in an adjacent pair of electrodes. In one aspect, electrodepairs 97 can be densely packed in order to maximize the transdermaltransfer rate. For example and not meant to be limiting, the density mayrange from 4-100 electrode sets/cm². In a further aspect, each electrodepair typically generates at least one micro-channel before a thresholdof current or total charge transfer is passed, in response to which, theswitching unit 91 causes current to the electrode pair to be terminatedor reduced.

Preferably, the spacing between electrodes in each electrode pair issmaller than about 0.1 mm, although, for example and not meant to belimiting, it may range from between about 0.1 mm to about 0.3 mm.Generally, the distance between the respective electrodes of anelectrode pair is set such that a desired electric field penetrationdepth is achieved. In one example, the desired electric fieldpenetration depth is substantially of the same magnitude as thethickness of the stratum corneum, so that the current mostly does notenter epidermal tissue underlying the stratum corneum. In this exemplaryaspect, maintaining the electrode spacing between about 0.01 mm andabout 0.1 mm, including additional spacing of 0.02, 0.03, 0.04, 0.05,0.06, 0.07, 0.08, and 0.09 mm, generates micro-channels therein thestratum corneum while substantially reducing damage, sensation and/orpain in the innervated dermis and in the epidermal tissue below thestratum corneum.

At any point in the skin in a vicinity of two electrodes placed thereon,the electric field generated between the electrodes can be viewed ashaving fundamentally two components: a component perpendicular to theskin, which generally causes current flow perpendicular to the skin; anda lateral component, which generally causes current flow parallel to theskin surface. An electric field at the base of the stratum corneumhaving a relatively large lateral component generates current flowpredominantly in the stratum corneum, with relatively little currentflow into the underlying epidermal tissue. Thus, in one aspect, tissueablation can be restricted to occur mostly in the stratum corneumHowever, it is contemplated that the means for forming at least onemicropore can be used to form micropores, i.e., micro-channels in thisexample, that extend to a desired penetration depth below the stratumcorneum layer.

In a further aspect, the electrode array is disconnected from theswitching unit or power source at substantially the same time asablation of the stratum corneum is completed. In one aspect, theswitching unit 91 can monitor current flow to the electrodes 96 andselectively terminates the flow to one or more electrodes upon adetermination that ablation of the underling tissue has occurred. Inthis exemplary aspect, the current flow to all of the electrodes in thearray is substantially terminated upon a determination by the switchingunit 91 that the underlying tissue under the electrode array has beenablated.

In yet another aspect, the substrate 40 can define at least one femaledepression 140 that is defined on the lower substrate surface 44. Inthis aspect, the at least one of female depression is configured tocooperate with a series of depressible elements 142 mounted on theinterface 30 of the applicator 20. The depressible elements are incommunication with the controller board of the applicator. In oneexemplary aspect, there are three depressible elements such that, in anexemplary operation, if a substrate having two female depressions ismounted to the interface, only one of the depressible elements of theapplicator would be depressed. In this example, the depression of onlyone of the three depressible elements would electrically communicate tothe controller board the respective size of the poration area of thesubstrate that is mounted on the interface. One would appreciate that,in this example, selective depression of the depressible elements cancommunicate varying sizes of the poration area of the respectivesubstrate.

In a further aspect of the invention, the delivery system 10 furthercomprises a first release liner 110 that has a top surface 112 and anopposed bottom surface 114. In one aspect, at least a portion of thebottom surface of the first release liner is connected to a portion ofthe upper substrate surface 42. In another aspect, the system cancomprise an adhesive layer 116 positioned therebetween the upper surfaceof the substrate 40 and the bottom surface 114 of the first releaseliner to connect the substrate 40 to the first release liner 110. In oneaspect, an edge portion of first release liner is spaced a predetermineddistance from the poration area of the substrate. Optionally, the edgeportion of the first release liner is positioned substantially adjacentto a portion of the ridge formed on the upper substrate surface. In thisaspect, if the substrate defines the female depression in the uppersubstrate surface, the adhesive layer can be positioned adjacent aportion of the ridge of the female depression and the edge portion ofthe first release liner can also be positioned adjacent the portion ofthe ridge. In a further aspect, the patch 100 is selectively removablefrom the top surface 112 of the first release liner.

In a further aspect, the patch 100 can comprise a backing layer 102 anda reservoir 104 mounted to a portion of the backing layer. The reservoir104 is configured for releaseably containing the at least one permeantfor delivery into the tissue membrane of the subject via the formedmicropores. In one aspect, the reservoir 104 is mounted on a portion ofa lower surface 106 of the backing layer 102. As shown in the figures,in a connected position, a first portion 107 of the backing layer 102 isreleaseably mounted to the top surface 112 of the first release liner inspaced registration with the poration area 76 of the substrate 40.Further, in the connected position, a second portion 108 of the backinglayer 102 is folded back into a folded position. As one skilled in theart will appreciate, the lower surface 106 of the second portion 108 ofthe backing layer faces outwardly away from the upper substrate surface42 of the substrate in the folded position.

In a further aspect, the patch 100 can comprise a skin adhesive layer103 disposed on at least a portion of the lower surface 106 of thebacking layer of the patch such that the patch can be selectivelyreleasably mounted to the tissue membrane of the subject. In anotheraspect, the delivery system 10 can further comprise a second releaseliner 120 that is releaseably mountable to a portion of the skinadhesive layer 103 that is disposed thereon the second portion of thebacking layer. Optionally, an adhesive anchor layer 105, such as, forexample, double-sided adhesive and the like, can be mounted onto aportion of the filament array backing layer 74. In this aspect, thesecond release liner can be releaseably mounted to a portion of the skinadhesive layer 103 and the adhesive anchor layer.

The second release liner 120 provides a releasable cover that protectsthe otherwise exposed portion of the skin adhesive layer during storage.In this aspect, it is contemplated that the force required to remove thesecond release liner 120 from the skin adhesive layer 103 would be lessthan the force required to remove the first portion 107 of the backinglayer 102 from the top surface of the first release liner. Thus, thesecond release liner 120 can be removed from the patch 100 to expose thefolded over portion of the skin adhesive layer 103 without separatingthe patch 100 from the top surface 112 of the first release liner 110.In one aspect, a slit 122 can be defined therein a portion of the secondrelease liner 120 so that the second release liner can be readilygrasped and removed without imparting undo force to the underlyingstructure, i.e., without separating the patch 100 from the top surface112 of the first release liner 110.

In a further aspect, the top surface 112 of the first release liner canhave a release coating disposed thereon. The release coating can be anyconventional release coating comprising, for example and not meant to belimiting, silicone, platinum-catalyzed silicone, fluorosilicone,perfluorocarbon-based polymer, and the like.

In the connected position, in another aspect, the first portion 107 ofthe backing layer 102 is positioned in folded registration with theporation area 76 of the substrate 40. As exemplified in the figures, thefold can be spaced a predetermined distance from the poration area. Inone aspect, an edge of the reservoir 104 can be spaced substantiallyadjacent to the fold. Optionally, the reservoir can be spaced apredetermined distance from the fold. In the exemplified aspects, thereservoir is positioned in registration with the fold.

Referring now to FIGS. 4-6, a portion of the first portion 107 of thebacking layer 102 underlies the second portion 108 of the backing layerin the connected position. In a further aspect, the system 10 cancomprise a support member 130 that is positioned on portions of theupper surface 105 of the backing layer 102. In one aspect, the supportmember 130 has an edge surface 132. Further, in yet another aspect, thesupport member 130 can be releaseably mounted onto portions of the uppersurface 105 of the backing layer such that, in the connected position,the support member 130 is positioned between the upper surface 105 ofthe second portion 108 of the backing layer 102 and a portion of theupper surface 105 of the first portion 107 of the backing layer 102.

In one exemplified aspect, the edge surface 132 of the support member130 is positioned adjacent to the fold. In another aspect, the supportmember can comprise a substantially planar member. In this aspect, thesupport member can also comprise a portion that is folded back ontoitself to form the edge surface. Optionally, the portion that is foldedback onto itself can be secured into position with an adhesive.

In yet another exemplary aspect, the support member 130 can define atleast one hole 136 that extends therethough the support member. In thisaspect, the support member can be selectively secured relative to thebacking layer by heat welding overlapping portions of the backing layerthat are in registration with the at least one hole. In operation, whenthe patch is folded over onto the microporated tissue membrane, the heatwelded “tacks” would break apart to allow for the registration of thereservoir of the patch with the microporated portion of the tissuemembrane.

In a further exemplary aspect, the support member can define a pair ofopposed tabs that are configured to extend beyond the outer edge of thebacking layer. In one aspect, the tabs are secured to the uppersubstrate surface by the use of tape or the like that overlies therespective tabs and is secured to portions of the upper substratesurface. In one aspect, the portion of the tape that overlies therespective tabs can be non-adhesive such that the respective tabs arenot adhesively connected to the overlying tape.

In another exemplary aspect, the support member 130 can further comprisean adhesive tape 134 that is mounted therebetween a portion of theoverlapping first and second portions of the backing layer 102. In thisexample, the tape can be positioned between the upper surface 105 of thesecond portion 108 of the backing layer and a portion of the uppersurface 105 of the first portion 107 of the backing layer in theconnected position. In operation, when the patch 100 is folded over ontothe microporated portion of the tissue membrane, the adhesive tape 134is configured to release from the backing layer 102.

Referring to FIG. 20, an alternative embodiment of the delivery systemis schematically illustrated. In this aspect, the delivery system 10further comprises a first release liner 110 that has a top surface 112and an opposed bottom surface 114. In one aspect, at least a portion ofthe bottom surface of the first release liner is connected to a portionof the backing 74. In another aspect, the system can comprise anadhesive layer 116 positioned therebetween the upper surface of thebacking and the bottom surface 114 of the first release liner to connectthe backing 74 to the first release liner 110. In one aspect, an edgeportion of first release liner is spaced a predetermined distance fromthe poration area of the substrate. In a further aspect, the patch 100is selectively removable from the top surface 112 of the first releaseliner.

In a further aspect, the patch 100 can comprise a backing layer 102 anda reservoir 104 mounted to a portion of the backing layer. The reservoir104 is configured for releaseably containing the at least one permeantfor delivery into the tissue membrane of the subject via the formedmicropores. In one aspect, the reservoir 104 is mounted on a portion ofa lower surface 106 of the backing layer 102. As shown in the figures,in a connected position, a first portion 107 of the backing layer 102 isreleaseably mounted to the top surface 112 of the first release liner inspaced registration with the poration area of the substrate 40. Further,in the connected position, a second portion 108 of the backing layer 102is folded back into a folded position. As one skilled in the art willappreciate, the lower surface 106 of the second portion 108 of thebacking layer faces outwardly away from the upper substrate surface 42of the substrate in the folded position.

In a further aspect, the patch 100 can comprise a skin adhesive layer103 disposed on at least a portion of the lower surface 106 of thebacking layer of the patch such that the patch can be selectivelyreleasably mounted to the tissue membrane of the subject. In a furtheraspect, the delivery system can further comprise a patch backing film140 that is connected to a portion of the backing 74. In this aspect, anadhesive layer 142 can be attached to a first portion of the bottom sideof the patch backing film and a portion of the backing. Further, it iscontemplated that at least a portion of the upper surface of the backing102 layer of the patch can be selectively mounted to a second portion ofthe bottom side of the patch backing film 140. In yet another aspect,the delivery system 10 can further comprise a second release liner 120that is releaseably mountable to a portion of the top side of the patchbacking film. Optionally, a skin adhesive layer 144, such as, forexample, double-sided adhesive and the like, can be mounted therebetweenthe portion of the top side of the patch backing film, opposite thefirst portion of the bottom side of the patch backing film, and thesecond release liner. In another aspect, a portion of the second releaseliner can also be releasably connected to the second portion 108 of thebacking layer of the patch 100 in the connected position. In thisaspect, an adhesive layer 145 can be interposed between the folded overportion of the patch backing film.

In this aspect, it is contemplated that the force required to remove thesecond release liner 120 from the skin adhesive layer 144 would be lessthan the force required to remove the patch backing film from the topsurface of the first release liner. Thus, in this aspect, the secondrelease liner 120 can be removed from the patch 100 to expose the foldedover portion of the skin adhesive layer 103 without separating the patch100 from the top surface 112 of the first release liner 110.

In a further aspect, the top surface 112 of the first release liner canhave a release coating disposed thereon. The release coating can be anyconventional release coating comprising, for example and not meant to belimiting, silicone, platinum-catalyzed silicone, fluorosilicone,perfluorocarbon-based polymer, and the like.

In the connected position, in another aspect, the first portion 107 ofthe backing layer 102 is positioned in folded registration with theporation area 76 of the substrate 40. As exemplified in the figures, thefold can be spaced a predetermined distance from the poration area. Inone aspect, an edge of the reservoir 104 can be spaced substantiallyadjacent to the fold. Optionally, the reservoir can be spaced apredetermined distance from the fold. In the exemplified aspects, thereservoir is positioned in registration with the fold.

Referring to FIG. 21, an alternative embodiment of the delivery systemis partially schematically illustrated. In this aspect, the deliverysystem 10 further comprises a first release liner 110 that has a topsurface 112 and an opposed bottom surface 114. In one aspect, at least aportion of the bottom surface of the first release liner is connected toa portion of the backing 74. In another aspect, the system can comprisean adhesive layer 116 positioned therebetween the upper surface of thebacking and the bottom surface 114 of the first release liner to connectthe backing 74 to the first release liner 110. In one aspect, an edgeportion of first release liner is spaced a predetermined distance fromthe poration area of the substrate. In a further aspect, the patch 100is selectively removable from the top surface 112 of the first releaseliner.

In a further aspect, the patch 100 can comprise a backing layer 102 anda reservoir 104 mounted to a portion of the backing layer. The reservoir104 is configured for releaseably containing the at least one permeantfor delivery into the tissue membrane of the subject via the formedmicropores. In one aspect, the reservoir 104 is mounted on a portion ofa lower surface 106 of the backing layer 102 of the patch 100. As shownin the figures, in a connected position, a portion of the backing layer102 is releaseably mounted to the top surface 112 of the first releaseliner in spaced registration with the poration area of the substrate 40.

In a further aspect, the patch 100 can comprise a skin adhesive layer103 disposed on at least a portion of the lower surface 106 of thebacking layer 102 of the patch such that the patch can be selectivelyreleasably mounted to the tissue membrane of the subject. In a furtheraspect, the delivery system can further comprise a patch backing film140 that is connected to a portion of the top surface of the firstrelease liner. In this aspect, an adhesive layer 142 can be attached toa first portion of the bottom side of the patch backing film and aportion of the top surface of the first release liner. Further, it iscontemplated that a de-blocking member 146 can be mounted therebetween aportion of the bottom side of the adhesive layer and the top surface ofthe first release liner 110 such that it is easier to selectivelyseparate the adhesive layer 142 from the first release liner 110.Further, it is contemplated that at least a portion of the upper surfaceof the backing 102 layer of the patch can be selectively mounted to asecond portion of the bottom side of the patch backing film 140. In yetanother aspect, the delivery system 10 can further comprise a secondrelease liner 120 that is releaseably mountable to a portion of the topside of the patch backing film. Optionally, a skin adhesive layer 144,such as, for example, double-sided adhesive and the like, can be mountedtherebetween the portion of the top side of the patch backing film,opposite the first portion of the bottom side of the patch backing film,and the second release liner.

In this exemplary embodiment, it is contemplated that the force requiredto remove the second release liner 120 from the skin adhesive layer 144would be less than the force required to remove patch backing film fromthe top surface of the first release liner. Thus, the second releaseliner 120 can be removed from the patch 100 to expose the skin adhesivelayer without separating the patch 100 from the top surface 112 of thefirst release liner 110.

In a further aspect, the top surface 112 of the first release liner canhave a release coating disposed thereon. The release coating can be anyconventional release coating comprising, for example and not meant to belimiting, silicone, platinum-catalyzed silicone, fluorosilicone,perfluorocarbon-based polymer, and the like.

In the connected position, in another aspect, the backing layer 102 ispositioned in folded registration with the poration area 76 of thesubstrate 40. As exemplified in the figures, the fold can be spaced apredetermined distance from the poration area. In one aspect, an edge ofthe reservoir 104 can be spaced substantially adjacent to the fold.Optionally, the reservoir can be spaced a predetermined distance fromthe fold. In the exemplified aspects, the reservoir is positioned inregistration with the fold.

In one exemplified aspect of the transdermal delivery system, thereservoir 104 comprises a designated area or chamber within the patch100 that is configured to contain a permeant for delivery through theformed artificial opening or micropore in the tissue or biologicalmembrane into the subject. In one aspect, it is contemplated that thereservoir can also comprise excipient compounds which enhance the effectof a bio-active permeant. Additionally, in various exemplified aspectsand not meant to be limiting, the reservoir may be comprised of anopen-volume space, a gel, a flat planar space which has been coated ortreated with a selected compound for subsequent release or reaction, ora permeable solid structure such as a porous polymer.

In an alternative embodiment, the reservoir 104 can comprise at leastone undissolved hydrophilic permeant disposed therein. When thereservoir is positioned in registration with the micropores throughoperation of the transdermal delivery system of the present invention,the hydrophilic permeant can come in contact with subcutaneous fluidwhen the bottom surface of the reservoir is in fluid communication withthe at least one formed micropore or pathway through the skin layer of asubject. Once an effective amount of subcutaneous fluid has come intocontact with the delivery reservoir, the fluid subsequently provides adiffusion path for transdermally delivering at least a portion of thepermeant contained in the reservoir through the skin and into thesubject.

The reservoir 104 of this aspect can comprise a non-biodegradable matrixwhich, as stated above, further comprises at least one hydrophilicpermeant disposed therein. The matrix component of the permeant deliveryreservoir is comprised of a non-biodegradable material or combination ofnon-biodegradable materials that are biocompatible for topicalapplication to the outer skin layer of a subject for extended permeantapplication periods. The non-biodegradable material can, in one aspect,account for approximately 20 weight % to approximately 80 weight % ofthe reservoir, including additional amounts as 25 weight %, 30 weight %,35 weight %, 40 weight %, 45 weight %, 50 weight %, 55 weight %, 60weight %, 65 weight %, 70 weight %, and 75 weight % of the reservoir,and including any range of weight percentages derived from these values.

In one aspect, the non-biodegradable matrix can comprise anon-biodegradable polymeric material or combination of polymericmaterials. In one aspect, the non-biodegradable polymeric material iswater-insoluble or hydrophobic. For example and without limitation, inone aspect, the non-biodegradable matrix can comprise an ethylene vinylacetate (EVA) co-polymer; polyethylene, polyethyl acrylate, andcopolymers of ethylene and ethyl acrylate, and any combination thereof.In one aspect, the matrix is comprised of an ethylene vinyl acetateco-polymer having a relative percentage of vinyl acetate in the range offrom 0% to approximately 60%, including additional vinyl acetatepercentages as approximately 0%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, and 60% and any range of percentages derived fromthese values. In still another aspect, the ethylene vinyl acetateco-polymer comprises approximately 28% vinyl acetate.

The hydrophilic permeant can comprise any chemical or biologicalmaterial, compound, or composition suitable for administration by theconventional methods previously known in the art and/or by the methodstaught in the present invention. To this end, the permeant can compriseany one or more components that would be desired to be administeredtransdermally. For example, the hydrophilic permeant can be selectedfrom a bioactive agent, a filler, an anti-healing agent, an osmoticagent, and any other conventionally known additive suitable forproviding or enhancing a desired transdermal delivery of a permeant. Inone aspect, the hydrophilic permeant can account for approximately 20weight % to approximately 80 weight % of the reservoir, includingadditional amounts as 25 weight %, 30 weight %, 35 weight %, 40 weight%, 45 weight %, 50 weight %, 55 weight %, 60 weight %, 65 weight %, 70weight %, and 75 weight % of the reservoir, and including any range ofweight percentages derived from these values.

In still another aspect, the bioactive agent can be present within thereservoir 104 as an undissolved anhydrous hydrophilic salt. To that end,as used herein, “hydrophilic salt” and similar terms include, withoutlimitation, an ionic form of a bioactive agent, drug, or pharmaceuticalagent, such as sodium, potassium, ammonium, trimethamine, or othercation salts thereof, sulfate or other anion salts thereof, acidaddition salts of basic drugs, and base addition salts of acidic drugs.Illustrative examples of such salts include sodium diclofenac, sodiumcromolyn, sodium acyclovir, sodium ampicillin, sodium warfarin,ketorolac tromethamine, amiloride HCl, ephedrine HCl, loxapine HCl,thiothixene HCl, trifluoperizine HCl, naltrexone HCl, naloxone HCl,nalbuphine HCl, buspirone HCl, bupriprion HCl, phenylephrine HCl,tolazoline HCl, chlorpheniramine maleate, phenylpropanolamine HCl,clonidine HCl, dextromethorphan HBr, metoprolol succinate, metoprololtartrate, epinephrine bitartrate, ketotofin fumarate, atropine sulfate,fentanyl citrate, apomorphine sulfate, propranolol HCl, pindolol HCl,lidocaine HCl, tetracycline HCl, oxytetracycline HCl, tetracaine HCl,dibucaine HCl, terbutaline sulfate, scopolamine HBr, brompheniraminemaleate and hydromorphone HCl.

In addition to one or more bioactive agents, the at least one permeantcan also comprise a bio-compatible filler, which can comprise any one ormore of an excipient, hydroscopic agent, osmotic agent, permeationenhancer, anti-healing agent, anti-clotting agent, anti-inflammatory,anti-microbial agents, re-epitheliating inhibitory agent, nitrous oxideproduction inhibitory agent, melanogenesis inhibitory agents, dosingagent, and the like. In one aspect, the bio-compatible filler canaccount for approximately 20 weight % to approximately 80 weight % ofthe reservoir, including additional amounts as 25 weight %, 30 weight %,35 weight %, 40 weight %, 45 weight %, 50 weight %, 55 weight %, 60weight %, 65 weight %, 70 weight %, and 75 weight % of the reservoir,and including any range of weight percentages derived from these values.

Further, as used herein, an anti-healing agent can include, for example,anti-coagulants, anti-inflammatory agents, agents that inhibit cellularmigration, re-epithelization inhibiting agents, and osmotic agents.Suitable anticoagulants can comprise, for example, heparin having amolecular weight from 3,000 to 12,000 daltons, pentosan polysulfate,citric acid, citrate salts, EDTA, and dextrans having a molecular weightfrom 2,000 to 10,000 daltons. Suitable anti-inflammatory agents cancomprise, for example, hydrocortisone sodium phosphate, betamethasonesodium phosphate, and triamcinolone sodium phosphate. Suitable agentsthat inhibit cellular migration can comprise, for example, lamininand/or its related peptides.

In one example of the reservoir 104, the at least one hydrophilicpermeant is typically disposed or otherwise loaded within thenon-biodegradable matrix. To this end, in an exemplary aspect, thedelivery reservoir can be configured such that it has a bottom surfacethat defines a plurality of conduits therein. According to this aspect,the undissolved hydrophilic permeant can be disposed therein at least aportion of the plurality of conduits of the matrix. As such, theexemplified delivery reservoir 104 is adapted to use subcutaneous fluidexuded from the skin to dissolve or suspend at least a portion of thepermeant disposed within the matrix to enable diffusion or transport ofthe permeant into the deeper layers of the skin.

Various mechanisms of transport can effect the dispersion and movementof the undissolved permeant from the reservoir into the skin tissues. Ingeneral, but not exclusively, a permeant disposed within the matrixbecomes available to the organism upon release by leaving themicro-particulate form and typically going into solution or suspension.Once in solution or suspension, diffusion can provide the transportmechanism for the micro-particulate permeant via the treated outerlayers and into or through the viable layers of the skin and into thesubject. As the process continues over time, the voids formed by thepermeant that leaves the reservoir and moves into the skin form channelspenetrating into the body of the reservoir thereby providing additionalaccess to more permeant than was initially present at the surface of thereservoir. Accordingly, by placing the reservoir 104 in communicationwith at least one formed pathway through the skin layer of a subject,subcutaneous fluid can provide an effective amount or level of hydrationto the reservoir to dissolve or suspend the permeant. As such, arelatively high concentration of permeant in solution or suspension canbe provided that is also in communication to the viable tissue layers ofthe skin.

Referring now to FIGS. 17-19, an exemplified aspect of the transdermalpermeant delivery system is shown connected to the skin of the subjectprior to the poration event. Here, the second release liner has beenremoved to expose a portion of the skin adhesive layer of the patch,which is shown in adhesive contact with the tissue membrane of thesubject. The applicator is subsequently actuated so that poration of thearea of the tissue membrane that underlies the poration area of thesubstrate occurs. In one exemplified aspect, the actuation of theapplicator causes an electrical stimulus to be delivered to the meansfor forming at least one micropore to cause the ablation of theunderlying tissue membrane. For example, the electrical stimulus can bedelivered to the filaments of the filament array to cause resistiveheating thereof and thermal ablation of the underlying tissue membrane.In a further aspect, if used, the actuation of the applicator caninitiate the source of vacuum such that a vacuum is delivered to theporation area via the conduit and associated channels. One wouldappreciate that the vacuum provided would act to draw the tissuemembrane into intimate contact with the means for forming the at leastone micropore mounted therein the poration area, such as, for example,the exposed portion of the filament array and would additionally serveto help secure the applicator to the tissue membrane during the courseof the microporation event.

After the micropores are formed, and as shown in FIG. 18, thetransdermal patch is separated from a portion of the transdermal poratorsystem. In operation, as the applicator is removed, the substrateremains mounted to the interface of the applicator and the patchseparates from the first release liner. In this configuration, the patchis secured to the tissue membrane by that portion of the backing layerthat had been previously secured to the tissue membrane after the secondrelease liner had been removed. The now exposed portions of the backinglayer and the reservoir face away from the underlying tissue membraneand are positioned such that the reservoir is registered about the foldwith the microporated area of the tissue membrane. Referring now to FIG.19, the patch is folded over with respect to the fold such that thetransdermal patch is positioned in registration with the microporatedarea of the subject's skin. After the patch is pressed into place, allother components of the system that may remain are removed to leave onlythe patch with the reservoir. As one will appreciate, the permeant thendiffuses from the reservoir through the micropores in the porated areaof the tissue into the body over a period of time. This period of timemay be minutes or days as appropriate for the specific permeant and useindication for the permeant.

Referring now to FIGS. 22-24, an exemplified aspect of the transdermalpermeant delivery system is shown connected to the skin of the subject.Here, after the micropores are formed, and as shown in FIG. 22, thetransdermal patch is separated from a portion of the transdermal poratorsystem. In operation, as the applicator is removed, the substrateremains mounted to the interface of the applicator and the patchseparates from the first release liner. In this configuration, the skinadhesive layer is secured to the tissue membrane and the patch ispositioned in registration with the formed micropores via the patchbacking film. Thus, the now exposed portions of the backing layer andthe reservoir of the patch face away from the underlying tissue membraneand are positioned such that the reservoir is registered about the foldwith the microporated area of the tissue membrane. Referring now to FIG.23, the patch backing film is folded over such that the patch is foldedwith respect to a fold such that the transdermal patch is positioned inregistration with the microporated area of the subject's skin. After thepatch is pressed into place, and as shown in FIG. 24, the patch backingfilm and all other components of the system that may remain are removedto leave only the patch with the reservoir in contact with the tissuemembrane. As one will appreciate, the permeant then diffuses from thereservoir through the micropores in the porated area of the tissue intothe body over a period of time. As noted above, this period of time maybe minutes or days as appropriate for the specific permeant and useindication for the permeant.

It is of course contemplated that the shapes of the patch that areexemplified in the figures are merely representative shapes and are notmeant to be limiting. The overall concept of the system is to provide analignment or registration mechanism which facilitates the application ofthe means for forming at least one micropore and then the subsequentstep of applying a permeant reservoir patch over the area in which themicropores are formed. As noted above, the means for forming at leastone micropore can comprise, without limitation, thermal, mechanical,optical, chemical, electrical or acoustical ablation means.

In a further aspect, the present inventive subject matter also includesa method for using such a device for administering a permeant to apatient in need thereof. The design of the present transdermal deliverysystem ensures proper registration of the reservoir of the patch overthe porated tissue membrane after application and actuation of afilament array. From the user's perspective, after the substrate ismounted to the applicator and the second release liner is removed, whatis actually multiple steps becomes a single step of applying theapplicator, actuating the applicator to form the micropores in theunderlying tissue, removing the applicator (which includes removing thesubstrate and the first release liner to expose the backing layer of thepatch), then folding the patch over in place to position the reservoirof the patch in registration with the porated area of the tissuemembrane, the set of operations being so intimately linked that theyquickly become a single process in the minds eye.

It is contemplated that the substrate and patch, positioned in theconnected position with the second release liner attached thereto can bepackaged individually in a single foil pack. Further, it is contemplatedthat this assembly can be formed and sterilized if needed, then filledwith the selected permeant (aseptically if needed) prior to being sealedinto the hermetic foil pack.

In one aspect and as described above, the interface to the applicator isconfigured to allow to applicator 20 to selectively deliver sufficientelectrical energy to create micropores in the outer layers of thepatient's skin. As described herein and for example and withoutlimitation, the formed micropores can be created for the purpose ofenabling the transdermal delivery of drugs or vaccines from a patch thatcan be selectively placed over the micropores.

In one aspect the applicator 20 and the interface 30 is configured tosupport multiple filament array sizes. For example and withoutlimitation, the applicator can support 1, 2, 3, 4, or more filamentarray sizes, such as, for example, 1, 2, 4 and 8 cm² array sizes. In afurther aspect, the applicator 20 can be configured to detect the sizeof the filament array of the attached substrate and can automaticallyconfigure itself for the detected size of the filament array. Thefollowing example is described with respect to a filament arrayembodiment of the means for forming at least one micropore, but oneskilled in the art will appreciate that it is contemplated that thedescribed modalities could be used for the selected modality.

In a further aspect, the applicator 20 can be configured to turn on orpower up upon the insertion of the substrate onto the interface of theapplicator. In another aspect, the applicator 20 can be configured toinitiate application of vacuum pressure when the substrate is mountedthereon the interface of the applicator. In this aspect, the applicationof vacuum pressure can be initiated automatically when the applicatordetermines that it is properly configured. In another aspect, it iscontemplated that the applicator could have a power button to initiatepower up of the applicator. However, optionally, it is contemplated thatpower up of the applicator can be initiated by insertion of thesubstrate 40, which “wakes-up” the applicator, which can then go througha series of self-tests, such as, for example and without limitation,battery voltage tests. In one aspect, if the applicator 20 passes theself-tests, a power light is illuminated and the applicator internallyprepares for an activation sequence. In one aspect, the activationsequence will charge high voltage capacitors, for example up to about˜230 volts. This voltage is set by hardware and, for example and withoutlimitation, can go up to 330 volts.

In operation, the user mounts the substrate into position on theapplication, which engages the electrical contacts when, for example,the substrate is snapped down into it's final mounted position. In oneaspect, the applicator 20 can continue to charge the high-voltagecapacitors during this time. In a further aspect, when the capacitorsare fully charged, a ready light can be illuminated. In another aspect,upon illumination of the ready light, the applicator can initiate avacuum pulsing sequence. In a further aspect, the applicator can furthercomprise a low battery indication and an error indication.

In one aspect, the user removes the release liner protecting theadhesive surrounding the filament array and positions the applicator onan appropriate skin site and the vacuum pump continues to pulse until anominal vacuum is achieved, such as, for example and not meant to belimiting, about ten inches Hg vacuum. An exemplary schematic of thevacuum circuit is shown in FIG. 29. Once an adequate vacuum seal isestablished, the applicator can be configured to send at least onecurrent pulse to the filament array. As noted herein, the filamentsprovide a thermal pulse of energy to the skin, which creates microporesin the skin. As exemplary illustrated herein, the user then removes theapplicator and substrate and folds over the registered patch onto themicroporated portion of the skin.

In an exemplary embodiment, and as shown in FIG. 25, the applicatorelectronics can be exemplarily broken down into two functional blocks—acontroller or microprocessor control circuit and the applicator powerdelivery circuits. In one aspect, the filament array can require, forexample and without limitation, approximately 120 amps for a fewmilliseconds. However, it is contemplated that other current levels canbe optionally selected. For example, as one skilled in the art willappreciate, depending on the filament array size and usecharacteristics, the current delivery operating point may utilizepulse-width modulation to regulate the effective energy delivered to thefilament array. In one aspect, peak current delivery can influencewarm-up time of the filament array when applied to the skin.Consequently, an ensemble of pulse times in conjunction with controlledcurrent delivery can be used. In a further aspect, an additional ‘mode’contact can be added to assure that the applicator recognizes thedesignated filament array size and rejects combinations of contactsresulting from open electrical contacts.

In one embodiment and referring now to the circuit schematic illustratedin FIG. 25, a Buck converter in a constant current mode can be utilized.Buffer capacitors store the current-source energy and feed a half-bridgetransforming function. In this aspect, the secondary of the transformeris configured to provide energy to the filament array circuit. Oneskilled in the art will appreciate that the exemplified control blocksare commercially-available integrated circuits and the whole circuit isenabled under microprocessor control. The exemplified circuit supportsseveral possible filament array circuits including, for example,switched banks.

Referring now to FIG. 26, a schematic of an exemplary power circuit isillustrated. As mentioned above, energy can be first stored as highvoltage in at least one flash capacitor. Once the capacitor(s) havereached their desired voltage, the high current poration sequence canbegin. In one aspect, a constant-current source pulls a steady currentout of the high-voltage capacitors and temporarily stores this energy inat least one sequential buffer capacitor. In another aspect, ahalf-bridge switch-mode converter can then perform an impedance matchingfunction—transforming high-voltage and intermediate current energy intovery high-current and low voltage suitable for driving the filamentarray. In one example and not meant to be limiting, the secondarycurrents can be about 120 amps at between about 5-10 volts.

In a further aspect, and as one skilled in the art will appreciate, apower source, regulation and distribution methods are required. In theapplicator 20, it is contemplated that all of the required internalenergy can be sourced by two 3 Volt lithium batteries, which are easilyreplaced by the use.

As noted above, the applicator 20 can be configured so that the“insertion” of a substrate into the interface of the applicator “wakesup” the microprocessor of the applicator. Subsequently, the applicatorcan latch up the 3.3 Volt regulator. In this aspect, the microprocessorunlatches this control circuit when the applicator has served itsintended purpose or, alternatively, if a software generated time-outindicates that the applicator is idle. Optionally, certain errorconditions, such as, for example and without limitation, a dead batteryand/or software check-sum faults can also result in errors that willcause the unit to shut down.

An exemplary schematic of the microprocessor block diagram is shown inFIG. 28. The microprocessor exemplarily supports several functions suchas, without limitation: internal power control, user interface (buttons,lights, and beeper), applicator power control, vacuum, developmentinterface, manufacturing interface and diagnostics. The applicatordriving software is configured to support many system interfaces anddefines interaction between the applicator (including hardware andsoftware) and an external function. In a further aspect, the applicatorcan be configured to monitor the application power (via a feedbackcircuit) and will real-time adjust the application energy, i.e., theapplied pulse modulation. This aspect adjusts for variations in filamentarray electrical impedance.

Identified system interfaces can comprise, without limitation:functional test, programming interface and user interface. In oneaspect, the functional test executes if the serial interface is attachedand enabled and initiated. The test starts after startup diagnosticswhen the test user requests initiation. In one example, the functionaltest can utilize the beeper to indicate the result of the functionaltest where tone frequency indicates a 1 (high frequency tone) or 0 (lowfrequency tone) and position dependence in binary format identifiesspecific module test pass/fail results. Result codes are also displayedthrough the serial interface. Specific test module details and placevalue dependence are described later. For any functional test moduleresult that indicates a failure, the unit will generate a FT fail tonewhile flashing test codes. If all functional test modules pass, theprocessor-controlled LEDs will flash times while the unit generates a FTpass tone sequence (4 high frequency tones). Functional test modules caninclude:

-   -   1. Timer Test—checks timer function by verifying timer is        incrementing.    -   2. Memory Test—verify memory function by writing and reading        from selected locations in memory.    -   3. Charge Test—verify charge function by charging system to 100V        within 1 second.    -   4. Vacuum System Test—verify that vacuum threshold can be        reached to start activation.    -   5. ADC Test—verify function of ADC circuit and 3.3V supply by        reading AVREF. Result should be within 5% of 2.5 Volts    -   6. PWM Test—verify function of PWM by checking for completion of        programmed tone.    -   7. Battery Test—verify battery check circuit by confirming that        AVREF voltage is between 2.25 and 3.35 volts and battery voltage        is within 5.8-7.0 volts.    -   8. Watchdog Test—verify watchdog timer by setting error code to        functional test mode and allowing timeout.    -   9. Parameter Test—verify that parameter values match secondary        location.    -   10. Checksum Test—verify program integrity by comparing        generated 16 bit checksum to stored value.    -   11. CLK test generates a 1 millisecond pulse on CLK1 followed by        a 1 millisecond pulse on CLK2. Test verification will be        performed prior to final assembly.    -   12. Control and Status Signals Loopback test—Verify function of        main to secondary control and status signals if in Loopback Test        mode.

The microprocessor can exemplarily use a 2 wire interface forprogramming internal flash memory. In one aspect, the interface becomesactive when the microprocessor senses the programming interface. Oneskilled in the art will appreciate that when the programming interfaceis active the processor is under control of the programming interface.

In one example the applicator user interface can comprise a plurality ofprocessor controlled LEDs, a hardware controlled LED, a multi-tonespeaker, and a Power/Activate button. The processor controlled LEDs canbe configured to indicate battery status, error status, and/oractivation readiness. In one aspect, there can be one spare processorcontrolled LED. In this aspect, the hardware controlled LED can beconfigured to indicate system power status. The beeper can be used tosignify errors, good events, bad events, and/or information events.

In a further aspect, the applicator functions can be exemplarilyimplemented through control software that can be broken into tasks tofacilitate a modular approach. For example, the tasks can be broken downto the following:

-   -   Main—software entry point and top level task sequence    -   Initialization—device initialization and startup diagnostics    -   Monitoring—Prepare device for activation    -   Activation—checks for valid activation conditions and controls        delivery of energy to porator    -   Shutdown—updates error status and powers down device

The Applicator software can contain additional modular units tointerface to hardware and internal functions such as, for example andwithout limitation: User Interface (UI); Functional Test; Error Handler;Analog to Digital Conversion (ADC); Timers; Port I/O; and/orProgarammable Counter (PCA).

FIG. 30 schematically illustrates an exemplary a top level behavioralflow diagram of the software of the applicator.

1. A transdermal permeant delivery system for delivery of at least onepermeant into a tissue membrane of a subject, comprising: a disposablesubstrate having an upper substrate surface and defining a porationarea; a first release liner having a top surface and an opposed bottomsurface, wherein at least a portion of the bottom surface of the firstrelease liner is connected to the upper substrate surface; and a patchthat is selectively removable from the top surface of the first releaseliner, comprising: a backing layer having an upper surface and anopposed lower surface; and a reservoir mounted thereon a portion of thelower surface of the backing layer and configured for releaseablycontaining the at least one permeant; wherein, in a connected position,a first portion of the backing layer is releaseably mounted thereto thetop surface of the first release liner in spaced registration with theporation area of the substrate, and wherein, in the connected position,a second portion of the backing layer is folded back into a foldedposition, in which the lower surface of the second portion of thebacking layer faces outwardly away from the upper substrate surface ofthe substrate.
 2. The system of claim 1, wherein the patch furthercomprises a skin adhesive layer disposed thereon at least a portion ofthe lower surface of the backing layer of the patch.
 3. The system ofclaim 2, further comprising a second release liner that is releaseablymountable to a portion of the skin adhesive layer that is disposedthereon the second portion of the backing layer.
 4. The system of claim3, wherein the force required to remove the second release liner fromthe skin adhesive layer is less than the force required to remove thefirst portion of the backing layer from the top surface of the firstrelease liner.
 5. The system of claim 4, wherein the top surface of thefirst release liner has a release coating disposed thereon.
 6. Thesystem of claim 5, wherein the release coating is selected from a groupconsisting of: silicone, platinum-catalyzed silicone, fluorosilicone,and a perfluorocarbon-based polymer.
 7. The system of claims 4 or 5,further comprising an adhesive layer positioned therebetween the uppersurface of the substrate and the bottom surface of the first releaseliner.
 8. The system of claim 1, wherein, in a connected position, thefirst portion of the backing layer is positioned in folded registrationwith the poration area of the substrate.
 9. The system of claim 2,wherein the fold is spaced a predetermined distance from the porationarea.
 10. The system of claim 9, wherein an edge of the reservoir isspaced substantially adjacent to the fold.
 11. The system of claim 9,wherein the reservoir is spaced a predetermined distance from the fold.12. The system of claim 1, wherein, in the connected position, a portionof the first portion of the backing layer underlies the second portionof the backing layer.
 13. The system of claim 1, further comprising asupport member having an edge surface, wherein the support member isreleasably mounted thereon portions of the upper surface of the backinglayer such that, in the connected position, the support member ispositioned between the upper surface of the second portion of thebacking layer and a portion of the upper surface of the first portion ofthe backing layer.
 14. The system of claim 13, wherein the edge surfaceof the support member is positioned adjacent to the fold.
 15. The systemof claim 13, wherein the support member comprises a substantially planarmember having a portion that is folded back onto itself to form the edgesurface.
 16. The system of claim 15, wherein the portion that is foldedback onto itself is secured into position with an adhesive.
 17. Thesystem of claim 13, wherein the support member defines at least one holethat extends therethough the support member, and wherein the supportmember is selectively secured relative to the backing layer by heatwelding overlapping portions of the backing layer that are inregistration with the at least one hole.
 18. The system of claim 1,further comprising an adhesive tape positioned between the upper surfaceof the second portion of the backing layer and a portion of the uppersurface of the first portion of the backing layer, whereby, when thepatch is folded over onto the skin, the adhesive tape breaks away fromthe backing layer.
 19. The system of claim 3, wherein the substratedefines a conduit extending between a lower substrate surface and theupper substrate surface, and wherein an open end of the conduit isdefined thereon the poration area.
 20. The system of claim 19, whereinthe substrate defines at least one channel on the upper substratesurface, and wherein the at least one channel is defined therein theporation area.
 21. The system of claim 20, wherein the at least onechannel is in communication with the conduit.
 22. The system of claim21, wherein the substrate defines a ridge on the upper substrate surfaceof the substrate.
 23. The system of claim 1, wherein the substratedefines a plurality of female depressions on the lower substrate surfaceof the substrate.
 24. The system of claim 1, further comprising a meansfor forming at least one micropore in the tissue membrane mountedthereon the substrate, wherein at least a portion of the means forforming at least one micropore is positioned therein the poration area.25. The system of claim 24, wherein the means for forming at least onemicropore comprises at least one filament selected from the groupconsisting of: a wire conductor, a deposited conductive material, amachined conductive material, a laser cut conductive material, anadhesive foil, an electroplated material, a screen-printed material, andan etched conductive material.
 26. The system of claim 24, wherein themeans for forming at least one micropore applies a stimulus to the atleast one filament, said stimulus initiating formation of the at leastone micropore by the at least one filament.
 27. The system of claim 26,wherein said stimulus is a thermal pulse.
 28. The system of claim 26,wherein said stimulus is an electrical pulse.
 29. The system of claim26, wherein said stimulus is a RF pulse.
 30. The system of claim 25,wherein the substrate defines a pair of ports that extend from the lowersubstrate surface and overlie respective portions of the means forforming at least one micropore.
 31. The system of claim 26, wherein thesubstrate defines a pair of ports that extend from the lower substratesurface and overlie respective portions of the means for forming atleast one micropore.
 32. The system of claim 24, wherein the means forforming at least one micropore is selected from the group consisting of:a filament capable of conductively delivering thermal energy via directcontact to the tissue biological membrane to cause the ablation of someportion of that membrane deep enough to form the micropore, a probeelement capable of delivering electrical energy via direct contact to atissue membrane to cause ablation of some portion of said membrane deepenough to form the micropore, an electro-mechanical applicator, amicrolancet, an array of microneedles or lancets, a sonic energyablator, a laser ablation system, and a high-pressure fluid jetpuncturer.
 33. The system of claim 24, wherein the means for forming atleast one micropore comprises: a plurality of electrodes mountable inthe poration area of the substrate, which are adapted to be applied tothe skin of the subject at respective points; and a power source, whichis adapted to apply electrical energy between two or more of theplurality of electrodes, to cause ablation of an area of the stratumcorneum during a first time period, so as to facilitate passage of asubstance through the ablated area during a second time period,subsequent to the first time period.
 34. The system of claim 24, whereinthe means for forming at least one micropore comprises: a plurality ofelectrodes mountable in the poration area of the substrate, which areadapted to be applied to the skin of the subject at respective points;and a power source, which is adapted to apply, between two or more ofthe plurality of electrodes, an alternating electric current so as tocause ablation of the tissue membrane.
 35. The system of claim 1,wherein the at least one permeant is a drug or biologically activeingredient.
 36. The system of claim 24, further comprising an applicatorcomprising: a body defining an interior cavity; a controller boardcomprising driving electronics and a power source, wherein thecontroller board is positioned within the interior cavity; an interfacefor releasably receiving the substrate.
 37. The system of claim 36,wherein the applicator further comprises a source of vacuum, wherein theinterface defines a port in communication with the source of vacuum, andwherein, in a connected position in which the substrate is mountedthereto the interface, the port of the interface is in fluidcommunication with the conduit of the substrate.
 38. The system of claim36, wherein the controller board is configured for selective control ofthe means for forming the at least one micropore.
 39. The system ofclaim 36, wherein the applicator further comprises an anode and acathode in select communication with respective portions of the meansfor forming the at least one micropore.
 40. The system of claim 39,wherein the anode comprises an anode pin extending therefrom theinterface of the applicator and wherein the cathode comprises a cathodepin extending therefrom the interface of the applicator.
 41. The systemof claim 40, wherein, in the connected position, the anode pin and thecathode pin are in electrical communication with respective portions ofthe means for forming the at least one micropore.
 42. A transdermalpermeant delivery system for delivery of at least one permeant into atissue membrane of a subject, comprising: a disposable substrate havingan upper substrate surface and defining a poration area, the disposablesubstrate comprising a filament array having a plurality of filamentsthat are disposed in the poration area, wherein each filament isconfigured for forming a micropore in the tissue membrane; a firstrelease liner having a top surface and an opposed bottom surface,wherein at least a portion of the bottom surface of the first releaseliner is connected to the upper substrate surface; and a patch that isselectively removable from the top surface of the first release liner,comprising: a backing layer having an upper surface and an opposed lowersurface; and a reservoir mounted thereon a portion of the lower surfaceof the backing layer and configured for releaseably containing the atleast one permeant; wherein, in a connected position, a first portion ofthe backing layer is releaseably mounted thereto the top surface of thefirst release liner in spaced registration with the poration area of thesubstrate, and wherein, in the connected position, a second portion ofthe backing layer is folded back into a folded position, in which thelower surface of the second portion of the backing layer faces outwardlyaway from the upper substrate surface of the substrate.
 43. The systemof claim 42, wherein the filament array is mounted to a portion of theupper substrate surface, and wherein the substrate further comprises abacking that is configured for mounting to and overlying a top surfaceof the filament array such that a portion of the filament array in theporation area is exposed.
 44. The system of claim 43, wherein thesubstrate further comprises an adhesive layer disposed between thebacking and the filament array.
 45. The system of claim 42, wherein thefilament array is enclosed in the substrate, and wherein the portion ofthe filament array in the poration area is exposed.
 46. The system ofclaim 43, wherein the filament array is a bi-clad foil material.
 47. Thesystem of claim 46, wherein the bi-clad foil material comprises a layerof copper and an underlying layer of stainless steel.
 48. The system ofclaim 47, wherein the bi-clad foil material is between about 10 μm-300μm in a thickness dimension.
 49. The system of claim 48, wherein thelayer of stainless steel comprises between about 5 to about 25 percentof the thickness of the bi-clad foil material.
 50. The system of claim46, wherein the filament array is formed by a chemical photo-etchingprocess.
 51. The system of claim 50, wherein the filaments aresubstantially uniform.
 52. The system of claim 43, wherein the filamentarray comprises means for distributing energy to the filaments of thefilament array.
 53. The system of claim 52, wherein the means fordistributing energy to the filaments comprises at least one electricalbank, each electrical bank having associated filaments.
 54. The systemof claim 53, wherein the at least one electrical bank comprises aplurality of electrical banks.
 55. The system of claim 54, wherein theporation area has a first portion and a mirrored second portion, andwherein portions of each electrical bank are positioned in both thefirst and second portions of the poration area.
 56. The systems of claim42, wherein the patch further comprises a skin adhesive layer disposedthereon at least a portion of the lower surface of the backing layer ofthe patch.
 57. The system of claim 56, further comprising a secondrelease liner that is releaseably mountable to a portion of the skinadhesive layer that is disposed thereon the second portion of thebacking layer.
 58. The system of claim 57, wherein the force required toremove the second release liner from the skin adhesive layer is lessthan the force required to remove the first portion of the backing layerfrom the top surface of the first release liner.
 59. The system of claim58, wherein top surface of the first release liner has a release coatingdisposed thereon.
 60. The system of claims 58 or 59, further comprisingan adhesive layer positioned there between the upper substrate surfaceof the substrate and the bottom surface of the first release liner. 61.The system of claim 42, wherein, in the connected position, the firstportion of the backing layer is positioned in folded registration withthe poration area of the substrate.
 62. The system of claim 61, whereinthe fold is spaced a predetermined distance from the poration area. 63.The system of claim 62, wherein an edge of the reservoir is positionedadjacent to the fold.
 64. The system of claim 42, wherein, in theconnected position, a portion of the first portion of the backing layerunderlies the second portion of the backing layer.
 65. The system ofclaim 42, further comprising a support member having an edge surface,wherein the support member is releasably mounted thereon portions of theupper surface of the backing layer such that, in the connected position,the support member is positioned between the upper surface of the secondportion of the backing layer and a portion of the upper surface of thefirst portion of the backing layer.
 66. The system of claim 65, whereinthe edge surface of the support member is positioned adjacent to thefold.
 67. The system of claim 65, wherein the support member comprises asubstantially planar member having a portion that is folded back ontoitself to form the edge surface.
 68. The system of claim 67, wherein theportion that is folded back onto itself is secured into position with anadhesive.
 69. The system of claim 57, wherein the substrate defines aconduit extending between a lower substrate surface and the uppersubstrate surface, and wherein an open end of the conduit is defined onthe poration area.
 70. The system of claim 69, wherein the substratedefines at least one channel on the upper surface of the substrate,wherein the at least one channel is defined on the poration area, andwherein the at least one channel is in communication with the conduit.71. The system of claim 42, further comprising a means for applying astimulus to the plurality of filaments, said stimulus initiatingformation of micropores by each of the respective filaments.
 72. Thesystem of claim 71, wherein said stimulus is selected from a groupconsisting of a thermal pulse, an electrical pulse, and an RF pulse. 73.The system of claim 71, wherein the substrate defines a pair of portsthat extend from the lower surface and are in communication withrespective portions of the filament array.
 74. The system of claim 42,wherein the at least one permeant is a drug or biologically activeingredient.
 75. The system of claim 74, further comprising an applicatorcomprising: a body defining an interior cavity; a controller boardcomprising driving electronics and a power source, wherein thecontroller board is positioned within the interior cavity; an interfacefor releasably receiving the substrate.
 76. The system of claim 75,wherein the substrate defines at least one channel on the uppersubstrate surface of the substrate, the at least one channel underlyingthe poration area, wherein the applicator further comprises a source ofvacuum, wherein the interface defines a port in communication with thesource of vacuum, and wherein, in a connected position in which thesubstrate is mounted thereto the interface, the port of the interface isin fluid communication with the conduit of the substrate.
 77. The systemof claim 75, wherein the controller board is configured for selectivecontrol of the means for applying a stimulus.
 78. The system of claim77, wherein the applicator further comprises an anode and a cathode. 79.The system of claim 78, wherein, in the connected position, the anodeand the cathode are in electrical communication with respective portionsof the filament array.
 80. A transdermal permeant delivery system fordelivery of at least one permeant into a tissue membrane of a subject,comprising: a disposable substrate having an upper substrate surface anddefining a poration area, the disposable substrate comprising a filamentarray having a plurality of filaments that are disposed in the porationarea, wherein each filament is configured for forming a micropore in thetissue membrane; a first release liner having a top surface and anopposed bottom surface, wherein at least a portion of the bottom surfaceof the first release liner is connected to the upper substrate surface;and a patch that is selectively removable from the top surface of thefirst release liner, comprising: a backing layer having an upper surfaceand an opposed lower surface; and a reservoir mounted thereon a portionof the lower surface of the backing layer and configured for releaseablycontaining the at least one permeant; wherein, in a connected position,at least a portion of the backing layer of the patch is releaseablymounted thereto the top surface of the first release liner in spacedregistration with the poration area of the substrate.
 81. The system ofclaim 80, wherein the filament array is mounted to a portion of theupper substrate surface, and wherein the substrate further comprises abacking that is configured for mounting to and overlying a top surfaceof the filament array such that a portion of the filament array in theporation area is exposed; wherein the backing underlies at least aportion of the first release liner.
 82. The system of claim 80, whereinthe filament array is enclosed in the substrate, and wherein the portionof the filament array in the poration area is exposed.
 83. The system ofclaim 81, wherein the filament array is a bi-clad foil material.
 84. Thesystem of claim 83, wherein the bi-clad foil material comprises a layerof copper and an underlying layer of stainless steel.
 85. The system ofclaim 84, wherein the bi-clad foil material is between about 10 μm-300μm in a thickness dimension.
 86. The system of claim 85, wherein thelayer of stainless steel comprises between about 5 to about 25 percentof the thickness of the bi-clad foil material.
 87. The system of claim81, wherein the filaments are substantially uniform.
 88. The system ofclaim 81, wherein the filament array comprises means for distributingenergy to the filaments of the filament array.
 89. The system of claim88, wherein the means for distributing energy to the filaments comprisesat least one electrical bank, each electrical bank having associatedfilaments.
 90. The system of claim 89, wherein the at least oneelectrical bank comprises a plurality of electrical banks.
 91. Thesystem of claim 90, wherein the poration area has a first portion and amirrored second portion, and wherein portions of each electrical bankare positioned in both the first and second portions of the porationarea.
 92. The systems of claim 80, wherein the patch further comprises askin adhesive layer disposed thereon at least a portion of the lowersurface of the backing layer of the patch.